Pulmonary Fibrosis And/or Bone Marrow Failure, Telomere-Related, 3

A number sign (#) is used with this entry because of evidence that telomere-related pulmonary fibrosis and/or bone marrow failure-3 (PFBMFT3) is caused by heterozygous mutation in the RTEL1 gene (608833) on chromosome 20q13.

For a discussion of genetic heterogeneity of telomere-related pulmonary fibrosis and/or bone marrow failure, see PFBMFT1 (614742).

Clinical Features

Stuart et al. (2015) reported 5 unrelated families with susceptibility to pulmonary fibrosis and/or unspecified lung disease. Affected family members had shortened telomeres (less than 1-2% of control length). None were noted to have features of bone marrow failure.

Cogan et al. (2015) reported 9 families in which multiple individuals were diagnosed with interstitial pneumonia between 45 and 87 years of age (mean, 64.8 years). All affected and unaffected mutation carriers had extremely short telomeres, at least less than the tenth percentile for age. None of the families had a history or clinical features of bone marrow failure, hematopoietic malignancy, or dyskeratosis congenita.

Inheritance

The transmission pattern of telomere-related pulmonary fibrosis in the families reported by Stuart et al. (2015) was consistent with autosomal dominant inheritance and incomplete penetrance. There was also evidence of environmental influences, e.g., smoking and occupational factors.

Molecular Genetics

In affected members of 5 unrelated families with telomere-related pulmonary fibrosis, Stuart et al. (2015) identified 5 different heterozygous mutations in the RTEL1 gene (see, e.g., 608833.0014-608833.0017). The mutations were found by whole-exome sequencing of 99 probands with a family history of pulmonary fibrosis. Among all families, at least 5 clinically unaffected individuals carried a pathogenic mutation, consistent with incomplete penetrance. Functional studies of the variants were not performed.

Lamm et al. (2009) and Deng et al. (2013) reported that a relative of sibs with biallelic RTEL1 mutations, who carried a heterozygous mutation (M492I; 608833.0003), died of pulmonary fibrosis at age 58 years.

In 9 unrelated families with PFBMFT3, Cogan et al. (2015) identified 9 different heterozygous mutations in the RTEL1 gene (see, e.g., 608833.0002; 608833.0018-608833.0020). The mutation in the first family was found by whole-exome sequencing of 25 families; subsequent mutations were found by sequencing the RTEL1 gene in 163 additional kindreds with the disorder. Overall, RTEL1 mutations were identified in 9 (4.7%) of 188 families who underwent sequencing. Peripheral blood cells derived from mutation carriers showed shortened telomeres and increased T-circle formation compared to controls, consistent with a loss of RTEL1 function.